Age-related and pathological fractures continue to be a significant public health issue that affects more than 10 million Americans annually, and they cause substantial mortalities, morbidities, and economic costs. Currently, the risk of fracture is clinically assessed by bone mass as measured by bone mineral density (BMD), but there are substantial overlaps in the BMD of low and high fracture risk groups, suggesting that bone quality may play a significant role in the determination of bone fragility. Some aspects of bone quality are reflected through bone micro-architecture, microdamage accumulation, and bone matrix material properties (BMMP), and each has been shown to contribute significantly to bone fragility. The signaling of transforming growth factor-2 (TGF-2) regulates BMMP and whole-bone fracture resistance through the repression of Runx2, but the downstream targets of TGF-2 and Runx2 remain unknown. Matrix metalloproteinase-13 (MMP-13) is one possible pathway by which TGF-2 and Runx2 affect BMMP. Preliminary studies show that TGF-2 directly regulate MMP-13 in osteoblastic culture, and MMP-13 deficient mice show a phenotype of increased fragility in their long bones. Taken together, the preliminary data the MMP-13 could play a role in the TGF-2 regulation of bone fracture resistance. We thus hypothesize that matrix metalloproteinase-13 is a downstream target of TGF-2 in the regulation of bone matrix material properties. This proposal aims to identify molecular mechanisms that specify and regulate bone matrix material properties, with the long-term goal of harnessing this knowledge towards the diagnosis, treatment, and prevention of age-related and pathological fractures. PUBLIC HEALTH RELEVANCE: The research work proposed here aims to address the mechanisms of regulation of bone fracture resistance. The increased understanding of the role of matrix metalloproteinase-13 in the TGF-2 regulation of bone matrix material properties would allow the precise manipulation of the regulatory processes of healthy bone maintenance. Furthermore, the results may lead to improved therapies and strategies for the prevention and treatment of age-related and pathological bone fragility.